Novel stable beadlets of lipophilic nutrients

ABSTRACT

The invention disclosed in this application relates to novel stable beadlets of lipophilic nutrients comprising an inert core having a coating of stabilizing antioxidants, lipophilic nutrients, or mixtures thereof. The beadlets may be coated with one or more coatings to protect the lipophilic ingredients from the atmosphere, specifically the coatings can be used to protect against moisture and/or oxygen. The invention also relates to a process for the preparation of the stable beadlets. The beadlets can be used in medicines and dietary supplements intended to facilitate the reduced risk of macular degeneration, cataract, and several forms of cancer.

This application is a Continuation of application Ser. No. 12/686,045,filed Jan. 12, 2010, which is a Divisional of application Ser. No.10/901,748, filed Jul. 29, 2004, which applications are incorporatedherein by reference.

The present invention relates to novel beadlets of lipophilic nutrientsand a process for their preparation. The present invention, particularlyrelates to novel and stable beadlets of lipophilic nutrients, materials,or substances, particularly nutrients like carotenoids, tocopherols,tocotrienols, plant sterols and stanols, and lecithins, select omega-3fatty acids and poly-unsaturated fatty acids, more particularly novelbeadlets of lutein, lutein esters, zeaxanthin, zeaxanthin esters, and aprocess for their preparation.

BACKGROUND OF THE INVENTION

The role of nutrients and phytochemicals in the promotion of good healththrough nutrition has now been extended to the likely benefits such asprevention of cancer, and protection against many other chronic diseaseslike arthritis, coronary heart disease, osteoporosis, and possibly manyothers.

A number of phytochemical nutrients have a lipophilic characteristic,such as tocopherols, tocotrienols, carotenoids, plant sterols andstanols, and lecithins, select omega-3 fatty acids and polyunsaturatedfatty acids. The terms “lipophilic nutrient(s)” or “lipophilicphytochemical(s)” or “active lipophilic nutrient(s)” are interchangeablyused for describing these compounds singly or in combination with othersuch compounds, while describing the current invention. Lipophilicnutrients are a class of substances which exhibit an affinity towardsoily or fatty solvents or carriers. Lipophilic substances have a highersolubility in hydrocarbon solvents, such as hexane, and have poor watersolubility.

Tocopherols, tocotrienols and carotenoids are naturally occurringlipophilic micronutrients, suggested to play a role in the prevention ofseveral degenerative diseases. Plant sterols or stanols are naturallyoccurring lipophilic compounds structurally related to cholesterol foundin nuts, vegetable oils, seeds, cereals and beans. Lecithins are complexlipophilic mixtures of glyceride oils and phosphatides (includingphosphaptidylcholine, or PC) which are widely used in food-processing,and are now being used as dietary supplements for their possible role asa source of choline which is required for cell-membrane integrity andfor a wide variety of biochemical and neurochemical processes within thebody. Polyunsaturated fatty acids (such as linolenic acid,alpha-linolenic acid, and gamma-linolenic acid) and omega-3 fatty acids(such as AA, DHA and EPA) have a significant nutritional role to playwith several metabolic processes and healthy body function.

Carotenoids and other lipophilic nutrients are useful as nutritionalsupplements for the prevention/treatment of diseases, such as, severalforms of cancer, immunological disorders, eye disorders, skinmanifestations, inflammation, cardio-vascular disease etc. Theselipophilic nutrients are typically required to be administered dailythrough a suitable delivery system. There are several delivery systemssuch as emulsions and suspensions or oily solutions that are popularlyused currently along with solid delivery forms such as gelatin beadlets.

Many of these lipophilic phytochemicals and nutrients are sought to beincorporated in formulations of nutritional supplements in a stable,standardized form. While these are typically available in oily, waxy orviscous form, there is often a need to present these in a dry deliveryform, which provides standardized quantities of these phytochemicalswith adequate protection against destabilizing influences of light,moisture or oxygen, or from contact with other reactive components of amulti-ingredient nutrient supplement or health food.

Issues in Formulating Products with Lipophilic Nutrients 1. Difficultyin Developing Dry-Delivery Form:

Many nutritional formulations in the industry are in the form oftablets, capsules or dry-mixes. It is a major problem for formulatorsand manufacturers of such supplements to incorporate lipophilicnutrients such as carotenoids, vitamin E sources like tocopherols andtocotrienols, concentrated forms of PC-rich lecithins, phytosterols andplant stanols, various PUFA rich oils and omega-3 fatty acids singly orin combination with other nutrients into dry forms due to the oily, waxyor viscous nature of these products. Some options like spray driedpowders, granules or gelatin beadlets work only with select products,and do not necessarily function well under tabletting systems. Some ofthe challenges in using lipophilic nutrients are explained below:

-   -   a. Carotenoids tend to be unstable at room temperature, and        prone to degradation on exposure to light, heat, air and acidic        environment. Their life needs to be extended by the use of other        stabilizing anti-oxidants such as natural tocopherols, ascorbic        acid derivatives and citrate.    -   b. Another option for stabilizing carotenoids is by delivering        the same in an oil medium to provide the protective cover of the        oils along with naturally present, or added anti-oxidants. Dry        delivery forms are considered more difficult to stabilize.    -   c. Tocopherols and tocotrienols are typically found in an oily        medium in the presence of vegetable oils. Such oily products are        difficult to use except in the smallest of doses in dry delivery        forms such as tablets without the use of specialized        technologies to convert them to powders, granules or beadlets.    -   d. Lecithins rich in the active ingredient PC (20-95%) tend to        be viscous pastes or waxy masses which are not suitable for        directly compressible or free-flowing powders.    -   e. Phytosterols and plant stanols are oily products that have        typically been supplemented through fat based supplements.        Incorporating these into free flowing or directly compressible        dry delivery forms would significantly increase the number of        options for formulators and manufacturers of nutritional        supplements.    -   f. PUFAs, GLA and Omega-3 Fatty Acids are currently used        sparingly and infrequently in tablet and capsule based        supplements due to their oily nature. Conventional dry delivery        conversion technologies do not provide good solutions for free        flowing, directly compressible beadlets.

2. Difficulties in Stabilizing Lipophilic Nutrients:

By nature, carotenoids are unstable at room temperature. Their stabilityis affected by light, heat, air (oxygen) and acidic environment. It isknown that their stability can be enhanced by the addition of certainstabilizing antioxidants such as natural tocopherols, ascorbic acidderivatives and citrate.

Carotenoids and other lipophilic nutrients are typically used asingredients for nutritional supplement formulations either asdispersions in oil or as powders, granules or beadlets for makingtablets or filling in capsules. In the form of oil dispersion, thesenutrients are generally encapsulated in soft gelatin capsules. Some ofthese, such as carotenoids are also manufactured as cold waterdispersible powder for use in fruit juices and other aqueous beverages.Out of these three forms, beadlets have the advantage of being suitablefor further formulation into compressed tablets or encapsulated in hardgelatin capsules.

At present beadlets of carotenoids and other lipophilic nutrients aretypically manufactured by spray drying a mixture of said activenutrients and gelatin along with sucrose, and stabilizers. In suchbeadlets the carotenoid/lipid particles are protected from light andoxygen in the matrix of gelatin and sucrose formed during the spraydrying process in which matrix the carotenoid/lipoid particles areembedded. The spray-dried product is made less cohesive by covering withstarch.

Processes for the preparation of beadlets have been described innumerous references. Dry formulations of fat soluble vitamins have beendisclosed. Hahnlein et al. (U.S. Pat. No. 6,531,157). Starch-basedemulsions have also been proposed as a mechanism for incorporatingwater-immiscible substances into a homogenous composition. Eskins et al.(U.S. Pat. No. 5,882,713). See also, e.g., U.S. Pat. No. 3,998,753; U.S.Patent Application No. 2003/0064133, U.S. Pat. No. 4,254,100, U.S. Pat.No. 4,670,247, U.S. Pat. No. 4,929,774, U.S. Pat. No. 5,811,609, U.S.Pat. No. 6,093,348, U.S. Pat. No. 6,582,721, U.S. Pat. No. 5,849,345,and U.S. Pat. No. 6,663,900. Despite these methods, there remains adesire for a better way to formulate lipophilic substances into astable, usable form. The beadlets obtained by the above known processesdo not ensure stability to the active material either in the beadletform itself, or when formulated into tablets. In addition, none of thehitherto known methods of making beadlets provide desirable physicalcharacteristics, such as spherical, free flowing beadlets suitable fortabletting or capsule filling. Further, the beadlets produced byhitherto known methods do not prevent leaching of the active nutrientscontained in such beadlets when subjected to compression to formtablets.

Most of these processes employ gelatin, a protein isolated from thebones and muscles of the animals. In recent times, use of excipients ofanimal origin in herb-based nutraceuticals is considered undesirable bya large section of users. Due to poor digestibility, use of gelatinbased formulations have a limitation for use among the geriatricpopulation. Sometimes, lactose is used as an excipient in the mainbeadlet matrix due to its compressible nature, but its dairy product(animal) origin makes it unacceptable to many, and is thereforeconsidered to be undesirable.

At present, the nutraceutical industry needs:

-   -   a. a solid form of active ingredients (carotenoid and lipids),        such as beadlets, suitable for formulation into tablet,    -   b. beadlets from which the active ingredients do not leach out        when compressed into tablets,    -   c. beadlets which can be protected from light or oxygen or        moisture,    -   d. beadlets preferably free from excipients of animal origin        (including dairy products),    -   e. beadlets which can be produced conveniently using a simple        process and equipment that are common,    -   f. beadlets which have an appealing, uniformly spherical        appearance.

Thus, the formulation of oral delivery systems for lipophilic nutrients,particularly carotenoids such as lutein, lycopene, beta carotene,present a challenge to the pharmaceutical and food industries, due tothe oily nature and instability of the carotenoids/lipids.

By nature, carotenoids and lipophilic nutrients are unstable in presenceof oxygen and light. Therefore, they can be stabilised by theincorporation of certain stabilising antioxidants. To further enhancestability, the active nutrients (e.g. carotenoids, or lipophilicnutrients such as tocopherols or tocotrienols etc) can be coated withpolymer(s) that provide protection against the harmful effects ofoxygen, light and moisture.

Non-pareil seeds such as sugar spheres or globules, without the activeingredient, on which the active ingredient is coated, are a convenientform for the preparation of oral dosage forms such as tablets or hardgelatin capsule, of the active ingredient. The beadlets produced bycoating the active ingredient on the non-pareil seeds are uniformlyspherical in nature and can be used in a size as small as about 250microns. The active ingredient—loaded beadlets, having a generallyspherical shape, may further be uniformly coated with a polymericmaterial to modify the release or mask the bitter taste of the drug.

In fluidisation process, the medium of coating can either be aqueous ororganic. Attempts have been made in the past to apply fluid bedtechnology for preparing microcapsules of carotenoids using aqueouscoating process on crystalline sucrose. Such processes suffer fromdrawbacks such as use of high temperature (180.deg. F.), which are notsuitable for many heat sensitive products such as carotenoids.

Unfortunately, this method using organic solvent medium is notapplicable directly for the formation of beadlets of lipophilicnutrients, such as carotenoids, in spite of the above said advantages,due to their oily/waxy nature. Further these nutrients, when subjectedto fluidization, form a cohesive mass, which adversely affects thefluidization. Therefore a process employing fluid-bed system using anon-aqueous coating medium has hitherto not been considered possible ordemonstrated, for the preparation of beadlets of lipophilic nutrientssuch as carotenoids.

SUMMARY OF THE INVENTION

The present invention involves the coating of an inert core withlipophilic nutrients and/or stabilising antioxidants. The lipophilicnutrients and/or stabilising antioxidants can be supplied in an organicsolvent medium and applied to the inert core by fluidisation technique.The resulting beadlets can be successfully employed in pharmaceuticaland food industries.

According to the present invention, a process of coating an inert corewith lipophilic materials or nutrients, particularly carotenoids,employing a fluidised bed technique in an organic solvent medium ispossible. This was possible when we found that a solution of lipophilicnutrients, in a non-polar solvent when diluted with a polar solventforms a colloidal suspension. This colloidal suspension when subjectedto fluidisation using a fluid bed system employing an inert core did notform a cohesive mass and does not adversely affect the fluidisationprocess. On the contrary, the process resulted in the formation of inertcores uniformly coated with the lipophilic materials or nutrients in theform of uniformly spherical beadlets.

In other words, the fluidisation technique using a non-aqueous solventwhich hitherto was not considered as applicable for the formation ofbeadlets of lipophilic nutrients, has been made possible by the processdeveloped according to the present invention. This invention hasresulted in developing a new concept enabling incorporation of oilylipophilic matter into beadlets.

The formation of stable, uniformly coated free flowing sphericalbeadlets of lipophilic nutrients is a result of the combination of theuse of spherical inert cores (non-pareil seeds) and selected stabilisingantioxidants and coating the resulting combination with oxygen andmoisture barrier polymers to provide additional protection.

The stability of the beadlets of lipophilic nutrients achieved by thisinvention depends upon the judicious selection of the protective agentsand coatings, and process conditions described in this invention. Withthe use of appropriate packing of the beadlets, such as sealedcontainers, by which exposure of the beadlets to moisture or air can bediminished or even eliminated, with commercially acceptable storagetemperatures ranging from about 10 to about 30 degrees C., shelf lifeand stability of the actives for periods ranging from 6 months to 36months, or higher as may be required—and tested as per ICH guidelinesfor the same—are possible.

The spherical nature of the beadlets has several advantages such as,free flowing property which is required during tablet compression,enables compression of tablets using a compression force as high as 10kg/cm², superior release property, possibility of site specificcontrolled release of carotenoids and lipids, and consequently, higherbioavailability. The major advantage of using such technology is that itavoids the use of high temperature (above 50 degree C.) duringpreparation of beadlets and thus prevents degradation of heat-sensitivebioactive compounds. Another advantage of using spherical cores is thebroader range of beadlet size which can range between about 250 micronsto about 3.50 mm. The beadlet size can also be from about 250 microns toabout 2.0 mm. Another advantage of the present invention is that theinvention can be practiced using existing fluid-bed technology andequipment.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Accordingly, the present invention provides novel stable beadlets oflipophilic nutrients, which comprise an inert core having a coating of amixture of stabilizing antioxidants and a lipophilic nutrient ormixtures thereof.

The novel beadlets of the present invention are obtained by coating onelipophilic nutrient, or a mixture of such nutrients on a central inertcore to obtain uniform, generally spherical beadlets. The uniform,generally spherical, appearance of these beadlet provides excellent freeflowing characteristics, which are very desirable for manufacturing andformulating operations. These novel beadlets are convenient to use, andhave a stronger visual appeal. The novel beadlets of the presentinvention also may be stabilized synergistically with the use ofanti-oxidants and with the application of layers of polymeric materialsas coatings, preferably gelatin free, on the beadlets as barriers toprevent penetration of light, moisture and/or air. The beadlets of thepresent invention are well suited for use as directly compressibleingredients in tablets, or in two-piece capsules.

In one embodiment of the present invention the inert core may becomprised of any material that does not react with the lipophilicnutrient or carotenoid employed for coating. It can be selected fromnon-pareil seeds made of carbohydrates such as sugar, mannitol, starch,sago, or microcrystalline cellulose. More preferably, the core used maybe seeds such as sugar spheres, mannitol spheres, or the like. The inertcore can generally be in the form of a sphere, and can have a diameterfrom about 200 microns to about 3 mm and still yield a stable beadlet.The inert core can also have a diameter of about 200 microns to about1.5 mm.

One embodiment of the current invention includes lipophilic nutrients inthe coating. Lipophilic nutrients refers to a class of compounds thatshow an affinity towards oily or fatty solvents or carriers, such ashexane, or otherwise have a higher solubility in hydrocarbons thanwater, and may be used in the current invention. The beadlets cancomprise from about 1 wt. % to about 50 wt. % lipophilic nutrient.

In one embodiment of the present invention the lipophilic nutrients usedin the coating are carotenoids, tocopherols, tocotrienols, plant sterolsand stanols, and lecithins, select omega-3 fatty acids, andpoly-unsaturated fatty acids, or mixtures thereof. The lipophilicnutrients may comprise carotenoids such as lutein, lutein esters,zeaxanthin, alpha-carotene, beta-carotene, natural lutein or zeaxanthinesters, astaxanthin, or lycopene. The beadlets can contain a mixture ofthese substances as well. For instance, the stable beadlets can comprisexanthophyll esters containing lutein and zeaxanthin fatty acid esters inwhich about 90 wt. % to about 95 wt. % is trans-lutein esters, 0 wt. %to about 5 wt. % is cis-lutein esters and about 3.5 wt. % to about 6 wt.% is zeaxanthin esters. The beadlets can also comprise xanthophyllcrystals that comprise at least about 85 wt. % total xanthophylls inwhich at least about 90 wt. % is trans-lutein and/or zeaxanthin.

The beadlets may also contain lipophilic nutrients such as vitamin A,vitamin D, or vitamin E in the form of mixed tocopherols ortocotrienols; vitamin K, medium chain triglycerides, and the like, or amixture of such lipophilic nutrients. The lipophilic nutrients may alsocomprise lecithins such as mixtures of glyceride oils and phosphatides(including phosphaptidylcholine); plant stanols and/or sterols;polyunsaturated fatty acids such as linolenic acid, alpha-linolenicacid, and gamma-linoleic acid; omega-3 fatty acids such as AA, DHA andEPA; tocopherols such as α, β, χ, and γ tocopherols; tocotrienols suchas α, β, χ, and γ tocotrienols; vegetable oils such as soya oil,partially or fully hydrogenated soya oil, cotton oil, coconut oil,palm-kernel oil, maize oil, palm oil, sunflower oil, olive oil, sesameoil, linseed oil, hazelnut oil, walnut oils, safflower oil, corn oil,peanut oil, vegetable oils having an unsaturated long chain fatty acidcontent of about 30 wt. % to about 90 wt. %, or any blends or fractionsof these vegetable oils. The lipophilic nutrient can also be lipophilicsubstances that have diuretic and cosmetic application such as the oilsof avocado, pear, blackcurrant, borage, castor, evening primrose,wheat-germ, and the like. Of course, the lipophilic nutrients cancomprise combinations of the above ingredients. For instance, variouslipophilic nutrients could be diluted using one or more of the abovevegetable oils. One having ordinary skill in the art would understandthat this list of potential lipophilic substances is not exhaustive, andthere are many other lipophilic nutrients that offer medicinal,nutritional, pharmaceutical, or some other health or cosmetic benefit,which may also be utilized in the current invention.

In a preferred embodiment, the novel beadlets of the present inventionmay be in the form of spheres, globules and the like. The size of thebeadlets of the present invention may range between about 250 microns toabout 3.5 mm, more preferably about 250 microns to about 2.0 mm. By theterm spherical, the inventors intend to describe the free flowing natureof the beadlets, and do not intend to mean a geometrically sphericalbeadlet. The generally spherical shape of the beadlets provides for asubstantially free-flowing embodiment. The free-flowing capability ofthe beadlets can be determined by measuring the angle of repose. Theangle of repose is determined by allowing the beadlets to drop from afunnel held at a certain height and form a conical heap on a level, flatsurface. The angle of repose is the angle of the beadlet heap relativeto the horizontal, flat plane. The beadlets of the invention have anangle of repose preferably between about 20 to about 30 degrees, morepreferably about 22 to about 27 degrees, and most preferably betweenabout 23 to about 25 degrees.

In another preferred embodiment of the present invention the novelbeadlets may have a coating of a film of oxygen barrier polymer.

In another preferred embodiment of the present invention the novelbeadlets may also have another coating, over the oxygen barrier polymer,with a film of a moisture barrier polymer. One with skill in the artwill recognize that one coating may be used to provide both of theseattributes.

In a preferred embodiment, the coatings are gelatin-free, and includeonly naturally derived materials. Such naturally derived materials cancomprise components which can be derived or isolated from vegetables.

The polymer used for coating for providing protection to the lipophilicnutrient matrix against oxygen may be selected from hydroxy propylcellulose, hydroxy propyl methyl cellulose, methacrylate copolymers,polyvinyl pyrrolidone, ethyl cellulose, carboxymethyl cellulose,polyvinyl alcohol, and the like, or their mixtures. Their amount mayrange from about 1 to about 40% of the weight of beadlets.

The polymer which can be used for providing a barrier to the entry ofmoisture can be selected from carboxy methyl cellulose sodium, hydroxypropyl cellulose, hydroxy propyl methyl cellulose, methacrylatecopolymers, polyvinyl alcohol and the like. If present, the moisturebarrier polymer can account for about 1% to about 40% of the weight ofbeadlets. The beadlets can also comprise about 2 wt. % to about 20 wt. %moisture barrier polymer. It should be understood that a singlepolymeric coating may act as both a moisture and oxygen barrier. Ofcourse, two different coatings can be used to act as an oxygen barrierand as a moisture barrier, respectively.

The lipophilic nutrients can also be provided with stabilisingantioxidants. Some stabilising antioxidants which may be employed toform the mixture of the lipophilic nutrients include vitamin E acetate,natural tocopherols, ascorbyl palmitate, ascorbic acid, sodiumascorbate, citric acid, rosemary extract or rosemary oil, curcuminoids,green tea extract, ginger extract, carnosic acid, butylated hydroxyanisole, butylated hydroxy toluene and the like or their combinationsthereof. When present, their amount used may vary from about 0.1% toabout 20% by weight of the carotenoid, lipophilic nutrient, or lipidused. To ensure an even distribution in the beadlet, the lipophilicnutrient may be mixed with a stabilizing antioxidant prior to coating ofthe inert core.

The beadlets can contain other stabilisers, such as sorbic acid, sodiumbenzoate, sodium salicylate, EDTA, and the like or mixture thereof.

In another embodiment of the present invention there is provided aprocess for the preparation of the novel beadlets of lipophilicnutrients as defined above which comprises.

-   -   (i) forming a colloidal suspension of the desired lipophilic        nutrients by dissolving the same in a non-polar solvent and        diluting the resulting solution with a polar solvent.    -   (ii) mixing the colloidal suspension obtained with a stabilising        antioxidant,    -   (iii) spraying the resulting colloidal suspension on to inert        cores present in a fluid-bed system provided with a bottom spray        mechanism, at a temperature in the range of ambient temperature        to 45 degree C., at an atomisation pressure in the range of        about 0.5 to about 3 Kg/cm² and a spray rate in the range of        about 10 g/hour to about 600 g/hour, and    -   (iv) drying the beadlets formed at an atomisation pressure of        about 0.8 kg/cm² to about 1.2 kg/cm².

In still another embodiment of the present invention there is provided aprocess for the preparation of the beadlets of lutein or any othercarotenoid, which comprises:

-   -   (i) forming a colloidal suspension of desired carotenoid by        dissolving the carotenoid in a non polar solvent and diluting        the resulting solution with a polar solvent,    -   (ii) mixing the colloidal suspension obtained with a stabilising        antioxidant, (iii) spraying the resulting colloidal suspension        on to inert cores present in a fluid-bed system provided with a        bottom-spray mechanism at a temperature in the range of ambient        temperature to about 45 degree C., at an atomisation pressure in        the range of about 0.1 kg/cm² to about 3 kg/cm² and a spray rate        in the range of about 10 g/hour to about 600 g/hour, and    -   (iv) drying the resulting beadlets at an atomisation pressure of        about 0.8 Kg/cm² to about 1.2 Kg/cm².

Various parameters of this process can be modified. For instance, thecolloidal suspension can be sprayed at a bed temperature from about 25degree C. to about 40 degree C., or even from ambient temperature toabout 32 degree C. In addition, the atomization pressure during sprayingcan be from about 0.5 kg/cm² to about 3 kg/cm², or even from about 1.0kg/cm² to about 2.5 kg/cm².

In a preferred embodiment the non-polar solvents which may be used forpreparing the colloidal suspension of the lipophilic nutrient includemethylene chloride, chloroform, petroleum ether (low boiling), petroleumether (high boiling) or mixtures thereof.

In another preferred embodiment, the polar solvents, which may be usedfor preparing the colloidal suspension of the lipophilic nutrientinclude isopropyl alcohol, acetone, methanol, ethanol, acetonitrile ormixtures thereof.

The non-polar solvent and polar solvent can be used in varying ratios.For instance, the non-polar and polar solvents can comprise a mixture ofmethylene chloride and isopropyl alcohol at a ratio of about 1:1 toabout 0.1:1. The non-polar and polar solvents can also comprise amixture of methylene chloride and isopropyl alcohol at a ratio of about0.2:1 to about 2:1.

The lipophilic nutrients can be mixed with polar solvent directly. Itmay be noted that carotenoids or lipophilic nutrients are not completelysoluble in polar solvent. This means that only some part of thecarotenoid or lipophilic nutrient may form a suspension. This suspensionmay not be homogeneous due to the presence of large particles of theundispersed carotenoids or lipophilic nutrients. This suspension can befiltered to remove the solid materials and the resulting colloidalsuspension can be used for the fluidisation process.

Although such a process is possible and envisaged within the broad scopeof the present invention, the process is not economical and efficient.When carotenoids are mixed with polar solvent directly, some portion ofthe carotenoid forms colloidal suspension, where as a large portionremains as a lumpy, un-dispersed solid mass. One can filter such amixture and use only the colloidal dispersion portion for coating. Ifone follows this procedure, it is not always possible to load anadequate quantity of carotenoid, and therefore not economical. Thereforeit is desirable to first dissolve or disperse the carotenoid innon-polar solvent, and thereafter form a colloidal dispersion by theaddition of polar solvent.

The stabilising antioxidants used may include vitamin E acetate, naturaltocopherols, ascorbyl palmitate, ascorbic acid, sodium ascorbate, citricacid, rosemary extract or rosemary oil, curcuminoids, green tea extract,ginger extract, carnosic acid, butylated hydroxy anisole, butylatedhydroxy toluene and the like or combinations thereof. When thestabilising antioxidants are used, the amount used may vary from about0.1% to about 20% by weight of the carotenoid, lipophilic nutrient orlipid used. The stabilising oxidants may also contain other stabiliserswhich may include sorbic acid, sodium benzoate, sodium salicylate, EDTA,and the like or mixtures thereof.

Binding agents may be added along with the stabilising antioxidants forenhancing the efficiency of the coating. If used, the binding agentsused may include gum acacia, gum tragacanth, xanthan gum, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose (5cps), hydroxypropyl methyl cellulose (15 cps), cellulose or theirmixtures. Their amount used may range from about 0.1% to about 10% ofthe weight of the beadlets. It may be advantageous to mix the bindingagent with the colloidal suspension prior to spraying the suspension inthe fluid-bed system.

Disintegrating agents may also be used along with the binding agents. Ifsuch agents are used they may be selected from starch, cross-linkedpolyvinyl pyrrolidone, cross-carmelose sodium and sodium starchglycolate or mixtures thereof. Their amount used may range from about0.1% to about 5% of the weight of the beadlets. Disintegrating agentscan also be combined with stabiliser. For instance, the beadlets cancomprise from about 0.1 wt. % to about 20 wt. % stabiliser and/ordisintegrating agent. Of course, the beadlets can contain stabiliser,binding agent, and disintegrating agent.

In another preferred embodiment of the present invention, the novelbeadlets are provided with a coating of a layer of films of an oxygenbarrier polymer.

In yet another preferred embodiment of the present invention, the novelbeadlets are provided with another coating over the layer of the coatingof films of an oxygen barrier polymer, with a film of a moisture barrierpolymer.

The details of the invention are provided in the examples given belowwhich are given for illustrative purposes only and therefore should notbe construed to limit the scope of the invention which is defined by theclaims.

EXAMPLES Example 1 Preparation of Beadlets Containing Lutein from Petalsof Marigold Flower Step 1 Preparation of Xanthophyll Crystals

The preparation of xanthophyll esters concentrate is described in IndianPatent Application No. 622/Mas/2002, U.S. Pat. No. 6,737,535, and PCT/In02/00219, the disclosures of which are incorporated by reference herein,and is summarized as follows.

Commercial grade marigold oleoresin (57.98 g) containing 11.54%xanthophyll content (by spectrophotometric method) was mixed withpotassium isopropyl alcoholate (prepared by dissolving 15 g potassiumhydroxide in 175 ml isopropanol.) The saponification mixture was heatedand maintained at 70 degree C. for a period of 3 hours. The degree ofhydrolysis was monitored by HPLC during the saponification stage.Isopropanol was distilled off under reduced pressure and the solidsobtained were stirred with 230 ml of water at room temperature. Themixture was taken into a reparatory funnel and extracted with equalvolume of ethyl acetate (3 times). Ethyl acetate layer was collected andwashed with distilled water for removing the excess alkali, soapymaterials and other water-soluble impurities. The ethyl acetate layerwas distilled off under reduced pressure to get saponified crude extract(25.01 g).

This resultant crude extract (25.01 g) was subjected to purification bystirring with 100 ml of hexane/acetone mixture (80:20) at roomtemperature for 30 minutes, followed by filtration. The precipitate ofxanthophyll crystals obtained was washed with methanol. The resultingorange crystals were vacuum dried at ambient temperature for 72 hrs.

The yield of the xanthophyll crystals was 3.41% (1.98 g). Xanthophyllcontent was 86.23% by weight (as determined by UV/Vis spectrophotometry)out of which the contents of trans-lutein, zeaxanthin, and othercarotenoids were 91.43%, 6.40% and 2.17% respectively as determined byHPLC analysis.

Step 2—Conversion of Above Xanthophyll Crystals to Beadlets

Carotenoids in the form of Xanthophyll crystals as described in step 1 aabove (92 g, containing 86.23% Xanthophylls by weight (78.84%trans-lutein) were suspended in a mixture of 300 g isopropyl alcohol and800 g methylene chloride. A solution of 10 gm of Hydroxypropylmethylcellulose (5 cps) in 200 g isopropyl alcohol and 100 g methylenechloride was added to the above suspension along with 20 g naturaltocopherol, 40 g ascorbyl palmitate and 15 g sodium starch glycolate.The suspension was strained through 100 mesh filter.

300 g of non-pareil seeds made of sugar, were charged into a Uni-Glattfluid bed processor with bottom spray, and warmed for 30 minutes at 35degree C. The carotenoids suspension as prepared above was sprayed onthe non-pareil seeds at the rate of 500 g/hour. The bed temperature wasmaintained at 35 degree C. Atomization pressure of 1.2 kg/cm² wasmaintained. 470 g of carotenoid loaded beadlets showing 9.46%trans-lutein were obtained.

80 g of polymer mixture comprising 32 g of ethyl cellulose and 48 g ofhydroxypropyl methyl cellulose was dissolved in solvent mixturecomprising 500 g of methylene chloride and 1000 g of isopropanol. 8 g ofpolyethylene glycol 600 was added as plasticiser. With this solution thecoating was performed on carotenoid loaded non-pareil seeds in UniGlattfluid bed coater using bottom spray technology at a spray rate of 400 gper hour. An atomization speed of 1.2 kg/cm² was maintained. Bedtemperature of 38 degree C. was maintained through out the coatingprocess. 540 g of oxygen-barrier coated beadlets showing 8.51%trans-lutein content were obtained.

55 g of polyvinyl alcohol was dissolved in 300 g water, mixed with 6 gof polyethylene glycol 400 and 2 g of titanium dioxide and the mixturewas sprayed on oxygen-barrier coated non-pareil seeds using Uni-Glattfluid-bed coater using bottom spray mechanism. A bed temperature of 45degree C. was maintained during coating. Atomisation pressure of 1.5kg/cm² was maintained. A spray rate of 150 g/hour was used. 580 g ofmoisture barrier coated carotenoid beadlets showing 6.8% trans-luteincontent were obtained.

Example 2 Preparation of Beadlets Containing Free Lutein in OilSuspension from Petals of Marigold Flower

Lutemax® Free Lutein Oil Suspension (obtained from Marigold flowerpetals) (110 g free lutein oil suspension in 220 g safflower oil) wassuspended in a mixture of 150 g isopropyl alcohol and 800 g chloroform.A solution of 5 gm of hydroxypropylmethyl cellulose (15 cps) in 200 gisopropyl alcohol and 100 g methylene chloride was added to the abovesuspension along with 20 g natural tocopherol, 40 g ascorbyl palmitateand 15 g sodium starch glycolate. The suspension was strained through100 mesh filter.

250 g of non-pareil seeds made of sugar, were charged into a Uni-Glattfluid bed processor with bottom-spray, and warmed for 30 minutes at 35degree C. The carotenoid suspension as prepared above was sprayed on thenon-pareil seeds at the rate of 500 g/hour. The bed temperature wasmaintained at 35 degree C. Atomisation pressure of 1.2 kg/cm² wasmaintained. 510 g of carotenoid loaded beadlets showing 8.1%trans-lutein were obtained.

80 g of polymer mixture comprising 10 g of ethyl cellulose and 70 g ofhydroxypropyl methyl cellulose was dissolved in solvent mixturecomprising 500 g of methylene chloride and 1000 g of isopropyl alcohol,8 g of polyethylene glycol 600 was added as plasticiser. With thissolution the coating was performed on carotenoid loaded non-pareil seedsin Uni-Glatt fluid bed coater using bottom spray technology at a sprayrate of 400 g per hour. An atomization speed of 1.2 kg/cm² wasmaintained. Bed temperature of 38 degree C. was maintained through outthe coating process. 580 g of oxygen-barrier coated beadlets showing7.2% trans-lutein content were obtained.

60 g of sodium carboxymethyl cellulose dissolved in 300 g water, thenmixed with 6 g of Polyethylene glycol 400 and 2 g of titanium dioxidewas sprayed on oxygen-barrier coated non-pareil seeds using Uni-Glattfluid-bed coater using bottom spray mechanism. A bed temperature of 45degrees C. was maintained during coating. Atomisation pressure of 1.5kg/cm2 was maintained. A spray rate of 150 g/hour was used. 610 g ofmoisture barrier coated carotenoid beadlets showing 6.5% trans-luteincontent were obtained.

Example 3 Preparation of Beadlets Containing Lutein from Petals ofMarigold Flower

Lutemax® Free Lutein (92 g, containing 78.84% trans-lutein) wassuspended in a mixture of 100 g isopropyl alcohol and 900 g methylenechloride. A solution of 80 gm of polyvinyl pyrrolidone in 400 gisopropyl alcohol and 100 g methylene chloride was added to the abovesuspension along with 20 g natural tocopherol, 40 g ascorbyl palmitateand 15 g sodium starch glycolate. The suspension was strained through100 mesh filter.

300 g of non-pareil seeds made of sugar, were charged in to a Uni-Glattfluid bed processor with bottom spray, and warmed for 30 minutes at 35degree C. The carotenoid suspension as prepared above was sprayed on thenon-pareil seeds at the rate of 500 g/hour. The bed temperature wasmaintained at 35 degree C. Atomisation pressure of 1.2 kg/cm² wasmaintained. 550 g of carotenoid loaded beadlets showing 9% trans-luteinwere obtained.

80 g of polymer mixture comprising 32 g of ethyl cellulose and 48 g ofhydroxypropyl methyl cellulose was dissolved in solvent mixturecomprising 500 g of methylene chloride and 1000 g of isopropanol. 8 g ofpolyethylene glycol 600 was added as plasticiser. With this solution thecoating was performed on carotenoid loaded non-pareil seeds in Uni-Glattfluid bed coater using bottom spray technology at a spray rate of 400 gper hour. An atomization speed of 1.2 kg/cm² was maintained. Bedtemperature of 38 degree C. was maintained through out the coatingprocess. 600 g of oxygen-barrier coated beadlets showing 7.9%trans-lutein content were obtained.

60 g of sodium carboxymethyl cellulose dissolved in 300 g water, thenmixed with 6 g of Polyethylene glycol 400 and 2 g of titanium dioxidewas sprayed on oxygen-barrier coated non-pareil seeds using Uni-Glattfluid-bed coater using bottom spray mechanism. A bed temperature of 45degree C. was maintained during coating. Atomisation pressure of 1.5kg/cm² was maintained. A spray rate of 150 g/hour was used. 650 g ofmoisture barrier coated carotenoid beadlets showing 6.6% trans-luteincontent were obtained.

Example 4 Preparation of Beadlets Containing 25% Trans-Lutein fromPetals of Marigold Flower

Marigold extract (382 g, containing 75% trans-lutein) was suspended in amixture of 1200 g isopropyl alcohol and 2800 g methylene chloride. Asolution of 90 gm of hydroxypropylmethyl cellulose (5 cps) in 500 gisopropyl alcohol and 200 g methylene chloride was added to the abovesuspension along with 60 g natural tocopherol, 80 g ascorbyl palmitateand 15 g cross-carmellose. The suspension was strained through 100 meshfilter.

300 g of non-pareil seeds made of sugar, were charged in to a Uni-Glattfluid bed processor with bottom spray, and warmed for 30 minutes at 35degree C. The carotenoid suspension as prepared above was sprayed on thenon-pareil seeds at the rate of 500 g/hour. The bed temperature wasmaintained at 35 degree C. Atomisation pressure of 2 kg/cm² wasmaintained. 910 g of carotenoid loaded beadlets showing 29% trans-luteinwere obtained.

75 g of polymer mixture comprising 32 g of ethyl cellulose and 48 g ofhydroxypropyl methyl cellulose was dissolved in solvent mixturecomprising 500 g of methylene chloride and 1000 g of methanol. 8 g ofpolyethylene glycol 600 was added as plasticiser. With this solution thecoating was performed on carotenoid loaded non-pareil seeds in Uni-Glattfluid bed coater using bottom spray technology at a spray rate of 400 gper hour. An atomization speed of 2.2 kg/cm² was maintained. Bedtemperature of 38 degree C. was maintained through out the coatingprocess. 985 g of oxygen-barrier coated beadlets showing 27.1%trans-lutein content were obtained.

65 g of polyvinyl alcohol dissolved in 300 g water, then mixed with 6 gof Polyethylene glycol 400 and 2 g of titanium dioxide was sprayed onoxygen-barrier coated non-pareil seeds using Uni-Glatt fluid-bed coaterusing bottom spray mechanism. A bed temperature of 45 degree C. wasmaintained during coating. Atomisation pressure of 2.5 kg/cm² wasmaintained. A spray rate of 150 g/hour was used. 1040 g of moisturebarrier coated carotenoid beadlets showing 25.7% trans-lutein contentwere obtained.

Example 5 Step 1: Preparation of Xanthophyll Esters Concentrate

The preparation of xanthophyll esters concentrate is described in IndianPatent Application No. 420/Mas/2002, U.S. Pat. No. 6,737,535, and PCT/In02/00218, the disclosures of which are incorporated by reference herein,and is summarized as follows.

A weighed quantity of marigold oleoresin (150.3 g) with xanthophyllester content 23.10% and trans-lutein, cis-lutein and zeaxanthin areapercentage by HPLC 67.23, 22.08 and 5.18 respectively was transferredinto an Erlenmeyer flask (1000 ml) followed by the addition of 750 ml of2-propanone. This was stirred using a thermostatically controlledstirrer at 15 degree C. to 25 degree C. for a period of 5-10 hours.After an interval of every 2 hours sample was drawn, filtered and thedried precipitated material was analyzed for the ester content andtrans-:cis-ratio by HPLC. Finally when the desired degree of the purityhad been achieved the solution containing precipitate was filteredthrough a Buchner funnel and the precipitate was dried in vacuum drierat ambient temperature.

The yield of the resulting concentrate was 20.10 g (13.37%) and theanalysis showed xanthophyll ester content 59.26% assayed byspectrophotometric method, measuring at 474 nm. This xanthophyll estersconcentrate contained area percentage by HPLC, trans-lutein 92.71,cis-lutein 1.40 and zeaxanthin 5.11 respectively. On visual examination,this concentrate showed an improved orange red color as compared to thestarting material, which is dark brown in color.

Step 2. Preparation of Beadlets Containing Xanthophyll Esters andTrans-Lutein Esters from Petals of Marigold Flower

Xanthophyll esters concentrate (160 g, containing 59.26% xanthophyllsesters by weight-yielding 27.47% trans-lutein on hydrolysis) wassuspended in a mixture of 700 g isopropyl alcohol and 600 g methylenechloride. A solution of 80 gm of hydroxypropylmethyl cellulose (15 cps)in 400 g isopropyl alcohol and 100 g methylene chloride was added to theabove suspension along with 20 g natural tocopherol, 40 g ascorbylpalmitate and 20 g sodium starch glycolate. The suspension was strainedthrough 100 mesh filter.

320 g of non-pareil seeds made of sugar, were charged in to a Uni-Glattfluid bed processor with bottom spray, and warmed for 30 minutes at 35degree C. The carotenoid suspension as prepared above was sprayed on thenon-pareil seeds at the rate of 500 g/hour. The bed temperature wasmaintained at 35 degree C. Atomisation pressure of 1.2 kg/cm² wasmaintained. 600 g of carotenoid loaded beadlets showing 10.1%trans-lutein were obtained.

80 g of polymer mixture comprising 10 g of ethyl cellulose and 70 g ofhydroxypropyl methyl cellulose was dissolved in solvent mixturecomprising 500 g of methylene chloride and 1000 g of isopropanol. 8 g ofpolyethylene glycol 600 was added as plasticiser. With this solution thecoating was performed on carotenoid loaded non-pareil seeds in Uni-Glattfluid bed coater using bottom spray technology at a spray rate of 400 gper hour. An atomization speed of 1.2 kg/cm² was maintained. Bedtemperature of 38 degree C. was maintained through out the coatingprocess. 680 g of oxygen-barrier coated beadlets showing 8.67%trans-lutein content were obtained.

150 g of polyvinyl alcohol dissolved in 300 g water, then mixed with 6 gof polyethylene glycol 400 and 2 g of titanium dioxide was sprayed onoxygen-barrier coated non-pareil seeds using Uni-Glatt fluid-bed coaterusing bottom spray mechanism. A bed temperature of 45 degree C. wasmaintained during coating. Atomisation pressure of 1.5 kg/cm² wasmaintained. A spray rate of 150 g/hour was used. 810 g of moisturebarrier coated carotenoid beadlets showing 6.0% trans-lutein contentwere obtained.

Example 6 Preparation of Beadlets Containing Beta-Carotene

Beta-carotene (20% dispersion in palm oil) 160 g, was suspended in amixture of 900 g isopropyl alcohol and 800 g chloroform. A solution of80 gm of polyvinyl pyrrolidone in 400 g isopropyl alcohol and 100 gmethylene chloride was added to the above suspension along with 20 gnatural tocopherol, 40 g ascorbyl palmitate and 12 g starch. Thesuspension was strained through 100 mesh filter.

450 g of non-pareil seeds made of sugar, were charged in to a Uni-Glattfluid bed processor with bottom spray, and warmed for 30 minutes at 35degree C. The carotenoid suspension as prepared above was sprayed on thenon-pareil seeds at the rate of 500 g/hour. The bed temperature wasmaintained at 35 degree C. Atomisation pressure of 1.2 kg/cm² wasmaintained. 650 g of carotenoid loaded beadlets were obtained.

74 g of polymer mixture comprising 10 g of ethyl cellulose and 70 g ofhydroxypropyl methyl cellulose was dissolved in solvent mixturecomprising 500 g of methylene chloride and 1000 g of methanol. 8 g ofpolyethylene glycol 600 was added as plasticiser. With this solution thecoating was performed on carotenoid loaded non-pareil seeds in Uni-Glattfluid bed coater using bottom spray technology at a spray rate of 400 gper hour. An atomization speed of 1.2 kg/cm² was maintained. Bedtemperature of 38 degree C. was maintained through out the coatingprocess. 680 g of oxygen-barrier coated beadlets were obtained.

145 g of sodium carboxymethyl cellulose dissolved in 300 g water, thenmixed with 6 g of polyethylene glycol 400 and 2 g of titanium dioxidewas sprayed on oxygen-barrier coated non-pareil seeds using Uni-Glattfluid-bed coater using bottom spray mechanism. A bed temperature of 45degree C. was maintained during coating. Atomisation pressure of 1.5kg/cm² was maintained. A spray rate of 150 g hour was used. 810 g ofmoisture barrier coated carotenoid beadlets were obtained.

Example 7 Preparation of Beadlets Containing Lecithin

Lecithin (Epikuron 200, made by Degussa Bioactives, containing 95%phosphatidylcholine) 120 g, was dissolved in a mixture of 700 g ethanoland 800 g chloroform. A solution of 45 g of hydroxy propyl cellulose in400 g isopropyl alcohol and 100 g methylene chloride was added to theabove suspension along with 25 g cross-linked polyvinyl pyrrolidone. Thesuspension was strained through 100 mesh filter.

500 g of non-pareil seeds made of sugar, were charged in to a Uni-Glattfluid bed processor with bottom spray, and warmed for 30 minutes at 35degree C. The mixture suspension as prepared above was sprayed on thenon-pareil seeds at the rate of 500 g/hour. The bed temperature wasmaintained at 35 degrees C. Atomisation pressure of 2.9 kg/cm² wasmaintained. 680 g of lecithin loaded beadlets were obtained.

60 g of polymer mixture comprising 10 g of ethyl cellulose and 70 g ofhydroxypropyl methyl cellulose was dissolved in solvent mixturecomprising 500 g of methylene chloride and 1000 g of isopropyl alcohol.8 g of polyethylene glycol 600 was added as plasticiser. With thissolution the coating was performed on carotenoid loaded non-pareil seedsin Uni-Glatt fluid bed coater using bottom spray technology at a sprayrate of 400 g per hour. An atomization speed of 3 kg/cm² was maintained.Bed temperature of 45 degree C. was maintained through out the coatingprocess. 740 g of oxygen-barrier coated beadlets were obtained.

120 g of sodium carboxymethyl cellulose dissolved in 300 g water, thenmixed with 6 g of polyethylene glycol 400 and 2 g of titanium dioxidewas sprayed on oxygen-barrier coated non-pareil seeds using Uni-Glattfluid-bed coater using bottom spray mechanism. A bed temperature of 45degree C. was maintained during coating. Atomisation pressure of 1.5kg/cm² was maintained. A spray rate of 150 g/hour was used. 850 g ofmoisture barrier coated lecithin beadlets were obtained.

Example 8 Preparation of Beadlets Containing Natural Mixed Tocopherol inVegetable Oil

Natural tocopherols in sunflower oil (Tocoblend L50) 80 g, was suspendedin a mixture of 900 g isopropyl alcohol and 800 g chloroform. A solutionof 80 g of polyvinyl pyrrolidone in 400 g isopropyl alcohol and 100 gmethylene chloride was added to the above suspension along with 40 gascorbyl palmitate and 12 g starch. The suspension was strained through100 mesh filter.

400 g of non-pareil seeds made of sugar, were charged into a Uni-Glattfluid bed processor with bottom spray, and warmed for 30 minutes at 35degree C. The mixture as prepared above was sprayed on the non-pareilseeds at the rate of 500 g/hour. The bed temperature was maintained at35 degree C. Atomisation pressure of 1.2 kg/cm² was maintained. 580 g ofnatural tocopherol loaded beadlets were obtained.

70 g of polymer mixture comprising 10 g of ethyl cellulose and 70 g ofhydroxypropyl methyl cellulose was dissolved in solvent mixturecomprising 500 g of methylene chloride and 1000 g of isopropyl alcohol.8 g of polyethylene glycol 600 was added as plasticiser. With thissolution the coating was performed on carotenoid loaded non-pareil seedsin Uni-Glatt fluid bed coater using bottom spray technology at a sprayrate of 400 g per hour. An atomization speed of 1.2 kg/cm² wasmaintained. Bed temperature of 38 degree C. was maintained through outthe coating process. 650 g of oxygen-barrier coated beadlets wereobtained.

130 g of sodium carboxymethyl cellulose dissolved in 300 g water, thenmixed with 6 g of Polyethylene glycol 400 and 2 g of titanium dioxidewas sprayed on oxygen-barrier coated Non-pareil seeds using Uni-Glattfluid-bed coater using bottom spray mechanism. A bed temperature of 45degree C. was maintained during coating. Atomisation pressure of 1.5kg/cm² was maintained. A spray rate of 150 g/hour was used. 650 g ofmoisture barrier coated mixed tocopherol beadlets were obtained.

Example 9 Preparation of Beadlets Containing Soy Bean Oil

Soya bean oil, 120 g, was suspended in a mixture of 400 g isopropylalcohol and 800 g chloroform. A solution of 80 gm of polyvinylpyrrolidone in 400 g isopropyl alcohol and 100 g methylene chloride wasadded to the above suspension along with 12 g of starch. The suspensionwas strained through 100 mesh filter.

400 g of non-pareil seeds made of sugar, were charged in to a Uni-Glattfluid bed processor with bottom spray, and warmed for 30 minutes at 35degree C. The mixture as prepared above was sprayed on the non-pareilseeds at the rate of 500 g/hour. The bed temperature was maintained at35 degree C. Atomisation pressure of 1.2 kg/cm² was maintained. 590 g ofsoy oil loaded beadlets were obtained.

70 g of polymer mixture comprising 10 g of ethyl cellulose and 70 g ofhydroxypropyl methyl cellulose was dissolved in solvent mixturecomprising 500 g of methylene chloride and 1000 g isopropyl alcohol, 8 gof polyethylene glycol 600 was added as plasticiser. With this solutionthe coating was performed on oil-loaded non-pareil seeds in Uni-Glattfluid bed coater using bottom spray technology at a spray rate of 400 gper hour. An atomization speed of 1.2 kg/cm² was maintained. Bedtemperature of 38 degree C. was maintained through out the coatingprocess. 650 g of oxygen-barrier coated beadlets were obtained.

130 g of sodium carboxymethyl cellulose dissolved in 300 g water, thenmixed with 6 g of polyethylene glycol 400 and 2 g of titanium dioxidewas sprayed on oxygen-barrier coated non-pareil seeds using Uni-Glattfluid-bed coater using bottom spray mechanism. A bed temperature of 45degree C. was maintained during coating. Atomisation pressure of 1.5kg/cm² was maintained. A spray rate of 150 g/hour was used. 770 g ofmoisture barrier coated soy oil beadlets were obtained.

Preparation and Evaluation of Tablet Formulation of Beadlets

The beadlets of present invention (Examples 1-4) 32 g were mixed withdi-calcium phosphate 40 g, microcrystalline cellulose 20 g, sodiumstarch glycolate 2 g, hydroxypropyl cellulose 3 g, aerosil 1 g andtalcum 1 g. After uniform blending the powder mixture was compressedinto tablets of 500 mg weight with hardness of 10 kg/cm².

TABLE 1 Properties of tablets compressed with beadlets of inventionTablet Beadlet Angle of Disintegration Dissolution rate, sample no.Repose time, in minutes Friability, %. % Product of 23 degrees 0.5 0.471.5 Example 1 Product of 25 degrees 0.6 0.35 70.6 Example 2 Product of24 degrees 0.3 0.6 72.8 Example 3 Product of 24 degrees 1.2 0.5 73Example 4 Product of 25 degrees 1.3 0.4 71.8 Example 5

The flow property of the beadlets was assessed by determining the angleof repose under the method disclosed in Remington's PharmaceuticalSciences, 16th Ed., page 1545. The current invention can includebeadlets having an angle of repose between about 22 to about 27 degrees.Beadlets having an angle of repose between about 23 to about 25 degreesexhibit excellent flow properties. Accordingly, the beadlets can beformed to have an angle of repose between about 23 to about 25 degrees.

The tablets showed disintegration time, as determined by the proceduregiven in United States Pharmacopoeia USP23 page no. 1790, of less than 2minutes and friability, as determined by procedure given in USP 23 pageno 1981, of less than 1%. The dissolution rate was determined byprocedure given in USP 23 page no. 1791. The tablets showed dissolutionrate of more than 70%. When scored tablets were examined under scanningelectron microscopy, the beadlets were found to be spherical and intact.The cross-section beadlets recovered from the tablet when examined underscanning electron microscopy revealed that the polymer coatings couldwithstand the compression force during tabletting and are in intactcondition. No leaching of carotenoids into the tablet matrix wasvisible.

Stability Studies

The beadlet formulations of Example 1-4 were subjected to acceleratedstability studies at 40 degree C. and 75% relative humidity. Thebeadlets were analyzed for carotenoid content before and after 6 months.The result of the study is shown in the following Table 2.

TABLE 2 Accelerated Stability of Beadlets at 40 Degree C. and at 75%Relative Humidity (RH) Beadlet Initial analysis Final analysis Percentretention of sample t-lutein t-lutein t-lutein Example 1 6.8%  6.6%97.05% Example 2 6.5% 6.35% 97.69% Example 3 6.6% 6.48% 98.18% Example 425.7%  24.8%  96.5% Example 5 6.0% 5.92% 98.66%

The above study concludes that the beadlets prepared by the presentinvention provide adequate stability to the carotenoid contained inside.

1-47. (canceled)
 48. A tablet product, comprising: a tablet matrix;beadlets within the tablet matrix, the beadlets being intact within thetablet matrix, the beadlets comprise an inert generally spherical coreand a coating comprising a stabilizing antioxidant and a lipophilicnutrient, and the beadlets having an angle of repose between about 22degrees to about 27 degrees.
 49. The tablet product of claim 48, whereinthe lipophilic nutrient comprises one or more carotenoids.
 50. Thetablet product of claim 49, wherein the one or more carotenoids isselected from at least one from the group consisting of lutein, luteinesters, alpha-carotene, beta-carotene, zeaxanthin, zeaxanthin esters,astaxanthin, lycopene, and mixtures thereof.
 51. The tablet product ofclaim 48, wherein the coating comprises a binding agent, the coatingbeing applied on the inert generally spherical core as a colloidalsuspension that is formed by a solution of the stabilizing antioxidantand the lipophilic nutrient that is first dispersed in a non-polarsolvent, and then with addition of a polar solvent, and the colloidalsuspension is mixed with the binding agent, the coating being applied bya bottom-spray fluidizing-bed system.
 52. The tablet product of claim51, further comprising one or more of an oxygen barrier coating and amoisture barrier coating over the coating comprising the stabilizingantioxidant, lipophilic nutrient, and binding agent.
 53. The tabletproduct of claim 51, wherein the non-polar solvent is methylenechloride, the polar solvent is isopropyl alcohol, and the binding agentis hydroxypropylmethyl cellulose.
 54. The tablet product of claim 51,wherein a ratio of non-polar solvent to polar solvent ranges from about0.2:1 to about 2:1.
 55. The tablet product of claim 51, wherein theamount of the binding agent ranges from about 0.1% to about 10% of theweight of the beadlets.
 56. The tablet product of claim 52, wherein theoxygen barrier coating comprising an oxygen barrier polymer selectedfrom the group consisting of hydroxy propyl cellulose, hydroxy propylmethyl cellulose, methacrylate copolymers, polyvinyl pyrrolidone, ethylcellulose, carboxymethyl cellulose, polyvinyl alcohol, and mixturesthereof.
 57. The tablet product of claim 56, wherein the beadletscomprise about 1 wt. % to about 40 wt. % oxygen barrier coating.
 58. Thetablet product of claim 52, wherein the moisture barrier coatingcomprising a moisture barrier polymer selected from the group consistingof carboxymethyl cellulose sodium, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, methacrylate copolymers, polyvinylalcohol, and mixtures thereof.
 59. The tablet product of claim 58,wherein the beadlets comprise about 1 wt. % to about 40 wt. % moisturebarrier coating.
 60. The tablet product of claim 48, wherein the inertgenerally spherical core comprises a generally spherical sugar core. 61.The tablet product of claim 60, wherein the inert generally sphericalcore comprises a carbohydrate that does not react with the lipophilicnutrient, said carbohydrate is selected from the group consisting ofsugar, mannitol, starch, sago, and microcrystalline cellulose.
 62. Thetablet product of claim 48, wherein the beadlets contain 25 to 50 wt %of lipophilic nutrient.
 63. The tablet product of claim 48, wherein thelipophilic nutrient comprises xanthophyll esters containing lutein andzeaxanthin fatty acid esters in which about 90 wt. % to about 95 wt. %is trans-lutein esters, 0 wt. % to about 5 wt. % is cis-lutein estersand about 3.5 wt. % to about 6 wt. % is zeaxanthin esters.
 64. Thetablet product of claim 48, wherein the lipophilic nutrient comprisesxanthophyll crystals comprising at least about 85 wt. % totalxanthophylls in which at least about 90 wt. % is trans-lutein and/orzeaxanthin.
 65. The tablet product of claim 48, wherein the lipophilicnutrient comprises a lipid selected from the group consisting oflecithin, mixed tocopherols or tocotrienols, plant stanols orphytosterols.
 66. The tablet product of claim 48, wherein the lipophilicnutrient is mixed, before coating, with the stabilising antioxidantwherein the stabilising antioxidant comprises an antioxidant selectedfrom the group consisting of vitamin E acetate, natural tocopherols,ascorbyl palmitate, ascorbic acid, sodium ascorbate, citric acid,rosemary extract, rosemary oil, curcuminoids, green tea extract, gingerextract, carnosic acid, butylated hydroxy anisole, butylated hydroxytoluene, and combinations thereof.
 67. The tablet product of claim 48,wherein the beadlets comprise about 0.1 wt. % to about 20 wt. %stabilising antioxidant.
 68. The tablet product of claim 48, wherein thecoating comprises disintegrating agents.
 69. The tablet product of claim48, wherein the beadlets comprise from about 0.1 wt. % to about 5 wt. %disintegrating agent, said disintegrating agent comprising a materialselected from the group consisting of starch, cross-linked polyvinylpyrrolidone, cross-carmellose sodium, sodium starch glycolate, andmixtures thereof.
 70. The tablet product of claim 48, wherein thetablets have a dissolution rate of more than 70% and up to 73% underprocedure USP23.
 71. The tablet product of claim 48, wherein the tabletshave a friability of 0.35% to 0.6% under procedure USP23.
 72. The tabletproduct of claim 48, wherein the tablets have a disintegration time of0.5 minutes to 1.3 minutes under procedure USP23.
 73. The tablet productof claim 48, wherein the beadlets and the tablet matrix together formthe tablet product having a hardness of about 10 kg/cm².
 74. A processfor the preparation of a tablet product, comprising: preparing beadletsof lipophilic nutrients, the beadlets formed include an inert generallyspherical core and a coating comprising a stabilizing antioxidant and alipophilic nutrient, and the beadlets having an angle of repose betweenabout 22 degrees to about 27 degrees; mixing the beadlets to form apowder mixture; compressing the powder mixture to form a tablet product,the tablet product includes a tablet matrix with the beadlets intacttherein.
 75. The process of claim 74, wherein the preparation ofbeadlets comprise (i) forming a colloidal suspension of lipophilicnutrient by dissolving the lipophilic nutrient in a non-polar solventand diluting the resulting solution with a polar solvent; (ii) sprayingthe resulting colloidal suspension onto an inert core in a fluid-bedsystem provided with a bottom-spray mechanism at a temperature in therange of ambient temperature to 45 degree C., at an atomisation pressurein the range of about 0.1 kg/cm² to about 3 kg/cm² and a spray rate inthe range of about 10 g/hour to about 600 g/hour; and (iii) drying theresulting beadlets in the fluid-bed system at an atomisation pressure ofabout 0.8 kg/cm² to about 1.2 kg/cm².
 76. The process of claim 74,wherein the lipophilic nutrient comprises a compound selected from thegroup consisting of carotenoid, lipophilic vitamin, lipid, and mixturesthereof.
 77. The process as claimed in claim 74, wherein the lipophilicnutrient comprises a carotenoid selected from the group consisting oflutein, zeaxanthin, lutein esters, alpha-carotene, beta-carotene,zeaxanthin esters, astaxanthin, lycopene, and mixtures thereof.
 78. Theprocess as claimed in claim 74, wherein the lipophilic nutrientcomprises a lipophilic vitamin selected from the group consisting ofVitamin A, Vitamin D, Vitamin E as tocopherols or tocotrienols, VitaminK, and mixtures thereof.
 79. The process as claimed in claim 74, whereinthe lipophilic nutrient comprises a lipophilic nutrient selected fromthe group consisting of lecithin, mixed tocopherols or tocotrienols,plant sterols, plant stanols, omega 3 fatty acids, polyunsaturated fattyacids, and mixtures thereof.
 80. The process as claimed in claim 74,wherein the beadlets comprise about 1 wt. % to about 50 wt. % lipophilicnutrient.
 81. The process as claimed in claim 74, wherein the lipophilicnutrient is mixed with a stabilising antioxidant.
 82. The process asclaimed in claim 81, wherein the stabilising antioxidant comprises asubstance selected from the group consisting of vitamin E acetate,natural tocopherols, ascorbyl palmitate, ascorbic acid, sodiumascorbate, citric acid, rosemary extract, rosemary oil, curcuminoids,green tea extract, ginger extract, carnosic acid, butylated hydroxyanisole, butylated hydroxy toluene, and mixtures thereof.
 86. Theprocess as claimed in claim 74, wherein the inert core comprises acarbohydrate that does not react with the lipophilic nutrient and saidcarbohydrate is selected from the group consisting of sugar, mannitol,starch, sago, microcrystalline cellulose, and mixtures thereof.
 84. Theprocess as claimed in claim 75, wherein the non-polar solvent comprisesa solvent selected from the group consisting of methylene chloride,chloroform, petroleum ether (low boiling), petroleum ether (highboiling), and mixtures thereof and the polar solvent comprises a solventselected from the group consisting of isopropyl alcohol, acetone,methanol, ethanol, and acetonitrile, and mixtures thereof.
 85. Theprocess as claimed in claim 75, wherein the non-polar solvent comprisesmethylene chloride and the polar solvent comprises isopropyl alcohol andthe ratio of methylene chloride to isopropyl alcohol is between about1:1 and about 0.1:1.
 86. The process as claimed in claim 85, wherein theratio of methylene chloride to isopropyl alcohol ranges from about 0.2:1to about 2:1.
 87. The process as claimed in claim 74, wherein thebeadlets are provided with an oxygen barrier coating comprising oxygenbarrier polymer, said oxygen barrier polymer comprising a polymerselected from the group consisting of hydroxy propyl cellulose, hydroxypropyl methyl cellulose, methacrylate copolymers, polyvinyl pyrrolidone,ethyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, andmixtures thereof.
 88. The process as claimed in claim 87, wherein thebeadlets comprise about 1 wt. % to about 40 wt. % of the oxygen barriercoating.
 89. The process as claimed in claim 74, wherein the beadletsare provided with a moisture barrier coating comprising a moisturebarrier polymer selected from the group consisting of carboxy methylcellulose sodium, hydroxy propyl cellulose, hydroxy propyl methylcellulose, methacrylate copolymers, polyvinyl alcohol, and mixturesthereof.
 90. The process as claimed in claim 89, wherein the beadletscomprise about 1 wt. % to about 40 wt. % of the moisture barriercoating.
 91. The process as claimed in claim 89, wherein the moisturebarrier coating also acts as an oxygen barrier.
 92. The process asclaimed in claim 74, wherein a stabiliser and/or a disintegrating agentare added to the lipophilic nutrient.
 93. The process as claimed inclaim 74, wherein the beadlets comprise a stabiliser, said stabilisercomprising a compound selected from the group consisting of sorbic acid,sodium benzoate, sodium salicylate, EDTA, and mixtures thereof.
 94. Theprocess as claimed in claim 74, wherein the beadlets comprise adisintegrating agent, said disintegrating agent comprising a compoundselected from the group consisting of starch, cross-linked polyvinylpyrrolidone, cross-carmellose, sodium starch glycolate, and mixturesthereof.
 95. The process as claimed in claim 74, wherein the beadletscomprise about 0.1 wt. % to about 5 wt. % disintegrating agent.
 96. Theprocess as claimed in claim 74, wherein the beadlets comprise about 0.1wt. % to about 20 wt. % stabilizer and/or disintegrating agent.
 97. Theprocess as claimed in claim 75, wherein a binding agent is mixed withthe colloidal suspension before it is used for spraying in the fluidisedsystem, said binding agent comprising a compound selected from the groupconsisting of gum acacia, gum tragacanth, gum xanthan, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose (5cps), hydroxypropyl methyl cellulose (15 cps), and mixtures thereof. 98.The process as claimed in claim 97, wherein the binding agent ishydroxypropyl methyl cellulose and the beadlets comprise about 0.1 wt. %to about 10 wt. % binding agent.
 99. The process as claimed in claim 97,wherein a stabilizer and/or a disintegrating agent is used along withthe binding agent.
 100. The process as claimed in claim 75, wherein thecolloidal suspension is sprayed at a bed temperature ranging from about25 degree C. to about 40 degree C.
 101. The process as claimed in claim75, wherein the atomization pressure during spraying is in the range ofabout 0.5 kg/cm² to about 3 kg/cm².
 102. The process as claimed in claim74, wherein the tablet product has a hardness of about 10 kg/cm².